Compartment-specific regulation of NaV1.7 in sensory neurons after acute exposure to TNF-α
Sidharth Tyagi,
Grant P. Higerd-Rusli,
Mohammad-Reza Ghovanloo,
Fadia Dib-Hajj,
Peng Zhao,
Shujun Liu,
Dong-Hyun Kim,
Ji Seon Shim,
Kang-Sik Park,
Stephen G. Waxman,
Jin-Sung Choi,
Sulayman D. Dib-Hajj
Affiliations
Sidharth Tyagi
Medical Scientist Training Program, Yale School of Medicine, New Haven, CT 06511, USA; Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Corresponding author
Grant P. Higerd-Rusli
Medical Scientist Training Program, Yale School of Medicine, New Haven, CT 06511, USA; Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA
Mohammad-Reza Ghovanloo
Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA
Fadia Dib-Hajj
Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA
Peng Zhao
Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA
Shujun Liu
Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA
Dong-Hyun Kim
Integrated Research Institute of Pharmaceutical Science, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, South Korea; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea
Ji Seon Shim
Department of Physiology, Kyung Hee University School of Medicine, Seoul 02447, South Korea
Kang-Sik Park
Department of Physiology, Kyung Hee University School of Medicine, Seoul 02447, South Korea
Stephen G. Waxman
Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Corresponding author
Jin-Sung Choi
Integrated Research Institute of Pharmaceutical Science, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, South Korea; Corresponding author
Sulayman D. Dib-Hajj
Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Corresponding author
Summary: Tumor necrosis factor α (TNF-α) is a major pro-inflammatory cytokine, important in many diseases, that sensitizes nociceptors through its action on a variety of ion channels, including voltage-gated sodium (NaV) channels. We show here that TNF-α acutely upregulates sensory neuron excitability and current density of threshold channel NaV1.7. Using electrophysiological recordings and live imaging, we demonstrate that this effect on NaV1.7 is mediated by p38 MAPK and identify serine 110 in the channel’s N terminus as the phospho-acceptor site, which triggers NaV1.7 channel insertion into the somatic membrane. We also show that the N terminus of NaV1.7 is sufficient to mediate this effect. Although acute TNF-α treatment increases NaV1.7-carrying vesicle accumulation at axonal endings, we did not observe increased channel insertion into the axonal membrane. These results identify molecular determinants of TNF-α-mediated regulation of NaV1.7 in sensory neurons and demonstrate compartment-specific effects of TNF-α on channel insertion in the neuronal plasma membrane.
